Hepatitis C treatment using
sofosbuvir (Sovaldi) is highly
effective even for people with multiple factors traditionally associated with
poor response. Having four or more negative predictive factors, however, raises
the risk of post-treatment relapse, according to a report at the 49th annual meeting of the European
Association for the Study of the Liver (EASL) held recently in London.
The advent of direct-acting antiviral
agents (DAAs) has begun to revolutionise treatment for chronic hepatitis C. But
several aspects of treatment – including the optimal duration of therapy and the
best regimens for patients traditionally considered difficult to treat – are
not yet fully understood.
Graham Foster of Queen Mary University of London and colleagues looked at the
influence of various host and virus factors traditionally associated with poor
response to interferon-based therapy.
Glossary
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- regression
Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.
Interferon, formerly the mainstay of
treatment for chronic hepatitis C, works by stimulating the body's own immune
response against the virus. Direct-acting antivirals directly interfere with
different steps of the hepatitis C virus (HCV) lifecycle. Studies have shown
that some of the factors associated with poor response to interferon may not
have as much effect when using DAAs.
Traditional negative predictive
factors include:
- Viral genotype: HCV genotypes 1 and
4 have been considered harder to treat than genotypes 2 or 3.
- Viral load: high pre-treatment HCV
RNA (>800,000 IU/ml) is associated with poorer response.
- Sex: men do not respond as well as
women.
- Age: older people do not respond as
well as younger people.
- Race/ethnicity: people of African
descent (and Hispanic/Latino people in some studies) do not respond as well as
Caucasian or Asian people.
- Body weight: heavier people,
especially those classified as obese (body mass index >30), do not
respond as well.
- IL28B status: people who carry the
TT or CT genetic variations do not respond as well as those with the favourable
CC pattern.
- Liver damage: people with advanced
fibrosis (stage F3) and especially cirrhosis (F4) do not response as those with
absent to moderate fibrosis (F0-F2).
- HIV/HCV co-infection: people with
both HIV and HCV do not respond as well as those with HCV alone.
- Prior treatment: People who
previously showed modest or minimal response to prior interferon-based therapy
(partial and null responders) do not respond as well as previously untreated
(treatment-naive) people or those who previously responded but relapsed after
finishing treatment.
Sofosbuvir leads to high response
rates for most patient populations. However, a small proportion of people do
not achieve sustained virological response, or undetectable HCV RNA at 12 weeks
post-treatment (SVR12), which is considered a cure. In most cases this is due
to relapse, or viral rebound after treatment is finished.
Foster and his team performed a
retrospective meta-analysis of data from phase 2 and 3 clinical trials of
sofosbuvir, used with either pegylated interferon and ribavirin (ATOMIC,
NEUTRINO) or ribavirin alone (FISSION, POSITRON, FUSION, VALENCE).
The researchers first performed a
univariate analysis to see the effect of each factor by itself, then did a
multivariate analysis to look at how these factors interact. Finally, they
calculated cure rates for people with increasing numbers of negative predictive
factors.
The analysis included 339
treatment-naive patients with genotype 1 chronic hepatitis C treated with
sofosbuvir plus pegylated interferon and ribavirin for 12 weeks, 285 treatment-experienced
and treatment-naive patients with genotype 2 treated with sofosbuvir plus
ribavirin for 12 weeks, and 247 treatment-naive and treatment-experienced patients
with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks.
Overall, about 60% of participants
were men and about two-thirds were age 50 or older. Fifteen per cent of people
with genotype 1, 8% of people with genotype 2 and no patients with genotype 3
were black. Approximately 60 to 70% had unfavourable IL28B gene variants. About
16% of people with genotype 1 and 2 had cirrhosis, rising to 24% for those with
genotype 3. One-third with genotype 2 and 58% with genotype 3 were
treatment-experienced (previously treated people with genotype 1 were not
included). More than three-quarters had high baseline HCV viral load.
In a univariate regression analysis
of the combined data set, factors found to be significantly associated with
post-treatment relapse (p < 0.05) were: liver cirrhosis (odds ratio [OR]
4.3, or more than 4-fold higher risk), baseline HCV RNA >800,000 IU/ml
(OR 3.9), male sex (OR 3.5), weight over 75kg (OR 3.2), IL28B non-CC (OR 2.8),
prior treatment (OR 2.8) and age over 50 years (OR 1.9). The effects of black
race, Hispanic ethnicity and elevated baseline ALT were not statistically
significant.
Surprisingly, while having HCV
genotype 3 rather than 2 was a significant risk factor (OR 2.5), the
differences between genotype 1 vs 2
and between 3 vs 1 did not reach
statistical significance (p = 0.18 and 0.06, respectively). Nor did HCV subtype
1a vs 1b turn out to be significant
in a more restricted analysis of people
with genotype 1 (p = 0.14).
In a multivariate regression
analysis of the combined data set, only six factors were independently associated
with relapse: high baseline viral load (OR 4.7), cirrhosis (OR 4.0), IL28B
non-CC (OR 3.4), weight over 75kg (OR 2.5), prior treatment (OR 2.3) and male
sex (OR 2.3).
SVR12 rates were 100% for people
with zero or one negative predictive factor, above 99% for those with two
factors and 94% for those with three factors. After this, efficacy dropped off,
falling to 88% for those with four negative factors, 68% for those with five
factors and 57% for those with six factors.
Cure rates were 90% or higher for
all genotype groups with zero to three negative predictive factors. For those
with four or more factors, the effect was most pronounced among people with HCV
genotypes 1 or 3 (in fact, no genotype 1 patients had zero risk factors).
"Sofosbuvir-based regimens were
highly effective, even in patients with a combination of multiple negative
factors," the researchers concluded. "SVR12 rates were comparatively
lower in patients with five or six of the negative predictors."
"Patients need to have a cluster of poor
predictors to be at risk for failure," Graham Foster explained. He
suggested that these factors "may help guide us in an interferon-free
world" when deciding on what regimens to use and for how long.
Notably, this analysis is specific to sofosbuvir, an
HCV polymerase inhibitor. Other trials indicate that the negative predictive
factors which remain relevant may differ among the various DAAs.
Although HIV and HCV co-infection was not included in
this analysis, other studies have shown that people with HIV can respond to
interferon-free regimens as well as people with HCV alone, leading some experts
to suggest that people with co-infection should no longer be separated out as a
'special' or difficult-to-treat population.